Repair of damaged or defective bone which involves more than the healing of a simple fracture has used three approaches to supply the required bone tissue: In the simplest approach, a prosthesis, intended to be permanent, is placed as a substitute for missing bone, and provisions made to integrate the prosthesis into the skeletal structure of the host. Such bone replacements may be made of artificial materials such as biocompatible metals, or may constitute allografts derived from bone structure elsewhere in the subject. A slightly more complex approach has been to provide a matrix to support ingrowth of bone from surrounding healthy tissue with subsequent possible resorption of the matrix. A third approach has been to supply both a matrix and an osteogenic factor which biochemically induces the ingrowth with or without a cartilagenous intermediate.
The history of development of the last two approaches, often called, respectively, "conductive" and "inductive" repair, shows continuing progress toward biologically derived materials which are of sufficiently low immunogenicity to enable them to function without unfavorable side effects. Since collagen is the major organic component of bone, its use as, or in, a matrix for subsequent deposit of the mineral bone component by adjacent cells has been extensive. However, collagen per se contains "telopeptide" units which are immunogenic, and a great improvement with respect to collagen for use in such matrix construction has been the use of "atelopeptide" collagen. Removal or partial removal of the telopeptides and consequent suppression of the immunogenic response may be important as this improves the performance in conductive bone repair of collagen derived from species foreign to that of the host--i.e., using "xenogeneic" collagen. For human recipients, this is significant because porcine, bovine, or other mammalian sources may be used for the preparation, rather than cadavers or related human donors, thus providing a much more inexpensive and plentiful source of supply. (On the other hand, telopeptide-containing collagen may also be useful in some instances.)
Incompatibility problems are increased when inductive implants are used, as not only does the matrix need to be acceptably compatible with the host, but also the preparation of any factors which induce cartilage and bone formation. In earlier work, demineralized bone (DMB) was used as part of the implant preparation in order to provide a source of such factors. See, for example, U.S. Pat. Nos. 4,440,750 and 4,430,760. Various attempts have been made to purify, from bone, the factors, presumably protein, which are responsible for osteoinduction. U.S. Pat. Nos. 4,294,753 and 4,455,256 to Urist disclose a bone morphogenic protein (BMP) which is extracted from demineralized bone using urea or guanidine chloride, and then reprecipitated. Further purifications of this factor have been reported by Urist in Clin Orthop Rel Res (1982) 162:219; Science (1983) 220:680; and Proc Natl Acad Sci (USA) (1984) 81:371. The BMP reported by Urist has a molecular weight of 17,500-18,000 daltons and is unadsorbed to carboxymethyl cellulose (CMC) at pH 4.8.
Presumptively different osteogenic factor proteins were isolated from DMB and purified by Seyedin and Thomas (U.S. Pat. No. 4,434,094 and Ser. No. 630,938, filed 16 Jul. 1984, and assigned to the same assignee). The active factor(s) in these preparations are, unlike the Urist factor, adsorbed to CMC at pH 4.8. The preparations were sufficiently purified that xenogeneic hosts could accept them without an immune response.
Attempts have been made to combine sources of an osteoinductive factor with a biocompatible support. U.S. Pat. No. 4,440,750 (supra) discloses a reconstituted atelopeptide collagen preparation in combination with DMB, or a DMB extract. U.S. Pat. No. 4,394,370 to Jeffries discloses the combination of a collagen preparation (which, however, contains the telopeptides), and a crude extract of DMB. The Jeffries disclosure references the BMP of Urist, and while commenting that BMP is not species specific in its activity, exemplifies the use only of allogenic DMB as the starting material for the extract, presumably because of perceived problems with immunogenicity. Also, the Jeffries disclosure requires the use of a minimum of 5% DMB extract by weight in the compositions. The combination with collagen support was apparently not tested in vivo.
Reddi, et al, Proc Natl Acad Sci (1983) 69:1601 described the use of allogenic demineralized bone powder to evoke cartilage and bone formation in rat hosts. Sampath, T. K. et al (Proc Natl Acad Sci (USA)) have also suggested the combination of allogenic rat bone collagen powder (presumably lacking the osteogenic factor) and a low molecular weight osteogenesis factor (presumably that of Urist) to be effective in bone repair in rat subjects. Thus, while the osteogenesis factor was xenogeneic, the support provided by the conductive portion of the implant disclosed in the Sampath (supra) was allogenic.
Because of supply and cost considerations, it would be advantageous to provide an entirely xenogeneic osteoinductive support implant. In order to do this, it is necessary to provide a support for the effective disposition of an osteogenic protein, wherein both the support and protein are of acceptably low immunogenicity, and wherein the composition is effective in inducing bone growth.